BackgroundRegional anesthesia has been widely practiced with minimal risk of complications. The aim of this study was to compare the efficacy of nalbuphine and tramadol as separate adjuvants to lidocaine in intravenous regional anesthesia (IVRA) (Bier's block).Materials and methodsThis randomized double-blind controlled study was conducted in the Department of Anesthesia, Kasr Al Ainy Teaching Hospital, Cairo University, Egypt. Sixty patients, aged 20-60 years, ASA I-II, both sexes, scheduled for minor hand surgeries under IVRA were enrolled in the study. The patients were randomly allocated into three equal groups: group L (n = 20) received lidocaine in IVRA, group LT (n = 20) received lidocaine and tramadol mixture, and group LN (n = 20) received lidocaine and nalbuphine mixture. The onset, duration of both sensory and motor blocks, time to first analgesic request postoperatively, and complications related to the drugs or technique were recorded.ResultsThere was a statistically significant acceleration in the mean onsets with significant prolongation of the mean duration of sensory and motor blocks in group LT and group LN compared with group L (P < 0.05). The results observed in both groups were comparable. In addition, there was an increase in the mean time to first analgesic request in group LT and group LN compared with group L (P < 0.001). Group LN had the longest duration time of postoperative analgesia and this was statistically significant compared with group LT (P < 0.001). Complications were minimal and nonsignificant.ConclusionThe use of nalbuphine and tramadol as adjuvants to lidocaine in IVRA resulted in significant acceleration of the onset and prolongation of the duration of both sensory and motor blocks, with minimal insignificant complications. Both tramadol and nalbuphine effects were comparable.

Local intravenous anesthesia (Bier's block) is an effective, safe, and reliable technique with minimal recorded complications [1]. It can be used to perform local anesthesia for upper (hand and forearm) and lower limbs, simply by injecting a local anesthetic into the distal vein while using a proximal tourniquet to occlude the circulation [1]. Lidocaine became the local anesthetic of choice for intravenous regional anesthesia (IVRA) because of the lack of cardiac toxicity and neurotoxicity. The main problem that was faced by the anesthetists was the short anesthetic and analgesic duration of lidocaine. Hence, many additives were tried to overcome this problem and to prolong its duration. Muscle relaxants, ketamine, ketorolac, and opioids are examples of these adjuvants, and their effects have been studied in details [2]. In addition, clonidine and dexmedetomidine, when used as adjuvants in Bier's block, proved to be effective in decreasing the anesthetic requirements and prolonging the analgesic duration [2],[3]. Many theories explain that opioids might exert their peripheral action through peripheral opioid receptors. They might also have their own local anesthetic effect by blocking sodium channels at the peripheral nerve endings [4],[5].

Tramadol hydrochloride, a weak μ-receptor agonist opioid with a central analgesic effect, possesses a local anesthetic effect by blocking Na + channels at the peripheral nerve endings. It also results in the release of serotonin and inhibits the reuptake of norepinephrine [4]. Many studies have shown that the addition of tramadol to local anesthetics improved the quality and duration of analgesia and anesthesia of the block [5],[6].

Nalbuphine is a mixed k-agonist-μ-antagonist opioid of the phenanthrene series. It is chemically related to naloxone and oxymorphone. It activates the spinal and supraspinal opioid receptors leading to adequate analgesia with cardiovascular stability, minimal sedation, less respiratory depression, less physical dependence, as well as less nausea and vomiting. All these advantages were found to be because of lack of the agonist effect on μ-receptors [7],[8],[9]. Because of its cardiovascular stability and respiratory safety, nalbuphine has been studied in oral surgeries in patients with poor physical and general condition [10]. For these previous reasons, safety and efficacy of nalbuphine has been established in the clinical field [11],[12].

In this study, it was hypothesized that the addition of nalbuphine or tramadol hydrochloride to lidocaine in IVRA would accelerate the onset and would prolong the duration of anesthesia and analgesia together with prolongation of the time to first analgesic request with minimal side effects.

The aim of the study was to compare the anesthetic and analgesic efficacy of nalbuphine and tramadol when used separately as adjuvants to lidocaine during IVRA (Bier's block) with the effect of lidocaine alone. The onset, duration times of both sensory and motor blocks, hemodynamic changes, the time to first analgesic request, and any complications related to the use of the drugs or technique were also recorded.

Materials and methods

This randomized double-blind controlled study was conducted in Department of Anesthesia, Kasr Al Ainy Teaching Hospital, Cairo University, Egypt from January to October 2013. After approval from local ethics committee and taking informed written consents from all patients, 60 patients, aged 20-60 years, ASA I or II, both sexes, scheduled for minor hand surgeries (K-wires under image, fracture lower radius or ulna, carpal tunnel, fracture finger, closed reduction under anesthesia) under IVRA were enrolled in the study. The patients were randomly allocated into three equal groups using computer-based lists and then covered in closed envelopes. Group L (n = 20) received lidocaine as a sole agent in IVRA. Group LT (n = 20) received lidocaine and tramadol local anesthetic mixture in IVRA. Group LN (n = 20) received lidocaine and nalbuphine local anesthetic mixture in IVRA. In addition to the previous patient characteristics, only patients with International Normalized Ratio (INR) less than 1.5, no history of anticoagulation, no infection at the site of injection, and no active cardiac or chest diseases were included in the study.

Furthermore, patients who refused to participate, patients with active cardiac or chest disease, irritability, and hyperactivity, patients with failed proper communication as in mental retardation, history of opioid addiction, Raynaud's disease, sickle cell disease, and duration of operation more than 60 min were excluded from the study.

In the preoperative preparation room, intravenous 0.02 mg/kg midazolam was given to all patients. In the operative room, patients were fully monitored by ECG, noninvasive blood pressure, and pulse oximeter (SpO 2 ). All patients were informed about the anesthetic procedure in detail. Before the IVRA block, a 20-G cannula was applied to a distal vein of the same arm under surgery. The baseline sensory level was assessed by a simple pinprick test with a 25-G sterile needle to the forearm and hand on a three-point scale (2 = normal sensation, 1 = blunted sensation, and 0 = absence of sensation) [13]. The pain score was assessed on 10-point verbal rating scale (VRS, 0-10, where 10 is the maximum imaginable pain, whereas 0 states complete absence of pain) [14],[15]. A double pneumatic tourniquet was placed on the arm under surgery. The upper limb was elevated and exsanguinated, and then an Esmarch elastic bandage was tightly wrapped from the distal part of the limb and directed proximally. The proximal tourniquet was inflated to 50 mmHg above systole according to the Association of Surgical Technologists' Guidelines [16],[17]. The Esmarch bandage was then removed. Proper function of the tourniquet was assessed clinically by disappearance of the radial pulse and was confirmed by the absence of pulse oximeter waves on the monitor. The randomly assigned patients received an intravenous injection of a local anesthetic mixture according to its selected group.

The 22-G cannula was removed after injecting the local anesthetic solution. The block was allowed to take effect. The onset of both sensory and motor blocks was recorded. The onset time for sensory block (time started from injection of local intravenous mixture until a complete sensory block was achieved in all dermatomes, sensory score = 0) was assessed every 30 s after injection of the local anesthetic mixture using a standardized pinprick technique with a 22-G short beveled needle. The sensation was tested in the dermatomal distribution of the lateral, medial, antebrachial cutaneous, radial, median, and ulnar nerves. The onset time for motor block was defined as the time elapsed from injection of local anesthetic mixture till achieving a complete motor block. The motor power was tested by asking the patient to extend and flex his wrist and fingers at 30-s intervals, and complete motor block was recorded when no voluntary movement was present. After complete sensory and motor block, the distal cuff was inflated to 50 mmHg above systolic blood pressure, 15 min after the inflation of the proximal one and then the proximal cuff was deflated gradually. Continuous observation of the distal tourniquet was performed to avoid unnoticed slow deflation. The minimum time for distal cuff deflation was kept not less than 30 min after inflation and was not allowed to be left inflated for more than 60 min. Pain secondary to tourniquet was assessed at a 5-min interval using VRS (where 0 = no pain and 10 = worst pain imaginable). If VRS was at least 4, fentanyl (1 μg/kg) was given intravenously to relieve the pain. At the end of the operation, the tourniquet was deflated gradually, and the radial pulsation was checked clinically and confirmed by appearance of pulse oximeter waves. The mean blood pressure (MBP), mean heart rate, and SpO 2 were recorded for all patients. If there were any complications secondary to the drug used, they were treated accordingly. If hypotension occurred (MBP < 30% of preoperative baseline), it was treated with intravenous fluids and increments of ephedrine (30 mg ephedrine diluted in10 ml saline). Bradycardia (heart rate < 60 beats/min) was treated by atropine 0.01-0.02 mg/kg. The duration of both sensory and motor blocks, time to first analgesic request postoperatively, and any complications related to the use of different drugs or technique were also recorded.

The duration of sensory block (time elapsed from injection of local anesthetic mixture until complete sensory recovery after subtraction of onset time value) was assessed by the pinprick test for all dermatomes; complete recovery was recorded when the score was 2 in all dermatomes.

The duration of motor block (time elapsed from injection of local anesthetic mixture to complete motor recovery after deduction of the onset time value) was assessed by complete recovery of motor power, assessed by asking the patient to try to flex and extend his wrist and fingers at 30-s intervals. The complete motor recovery was recorded when all voluntary movements were shown at the end of surgery and after removal of the tourniquet.

After gradual deflation of the tourniquet, time to first analgesic request (defined as the time elapsed from injection of local anesthetic mixture to the first analgesic request postoperatively after subtraction of the sensory onset time) was assessed by the VRS, and analgesia was given to the patient when VRS was at least 4 in the form of cataflam (diclofenac potassium 50 mg oral tablets). Sedation following tourniquet removal was assessed by the Ramsay Sedation Scale (RSS 0-6) [18] at 10-min interval for 1 h [1 = patient is irritable; 2 = alert and calm; 3 = respond to commands; 4 = brisk response to light forehead (glabellar) tap or loud verbal sounds; 5 = sluggish response to light forehead (glabellar) tap or to loud verbal sounds; and 6 = no response to verbal sounds].

All drugs and equipments for the management of local anesthesia toxicity or ineffective block (convert to general anesthesia) were prepared and kept ready to use. When sensory and motor block was ensured, surgical intervention was allowed.

Statistical analysis

The primary outcome variable was postoperative analgesia. Given that the mean duration of postoperative analgesia of lidocaine in IVRA was reported in the study by Nasr and Waly [5] to be about 120 min, a total sample size of 57 patients randomly allocated into three equal groups (19 patients per group) had 90% power to detect an assumed clinically significant difference of 20% or more in the mean duration of postoperative analgesia (effect size f = 0.487, β error = 0.1, α error = 0.05). To compensate for possible dropout, 20 patients per group were included. Statistical power calculations were performed using computer program G*Power 3 for Windows (Franz Faul, Universitδt Kiel, Germany). Data were collected and analyzed using SPSS version 19.1 (Chicago, USA). Intergroup comparison was performed using analysis of variance. Within-group comparison was analyzed using repeated measures of analysis of variance. Ordinal data were expressed as mean ± SD. However, paired t-test was used whenever needed. Categorical data were expressed as frequency or n (%). The c2 -test or the Fisher exact test was used when appropriate. P-value less than 0.05 was considered significant.

Results

A total of 60 adult patients were enrolled in the study. They were randomly divided into three equal groups: group L (n = 20), group LT (n = 20), and group LN (n = 20). There were no statistically significant differences among the studied groups regarding the demographic characteristics and duration of surgery [Table 1]. There were no statistically significant differences regarding hemodynamic data among the studied groups [Table 2].

With respect to the mean onset of sensory block, there was a statistically significant acceleration in the mean sensory onset in group LT (P = 0.021) and group LN (P = 0.025) when compared with the control group L. However, these changes were statistically insignificant when both groups were compared together [Table 2].

The mean onset of motor block was comparable between group LT and group LN but showed more acceleration in both groups when compared with the control group L. This was statistically significant (P = 0.007 and 0.002 for group LT and group LN, respectively) [Table 2].

With respect to the duration of sensory and motor blocks, there was a statistically significant increase in both sensory and motor recovery times in group LT (P = 0.015 and 0.001, respectively) and group LN (P = 0.001, P < 0.001, respectively) when compared with the control group L. In contrast, there were no statistically significant differences between group LT and group LN when compared together [Table 2].

Regarding the mean time to first analgesic request, there was an increase in the mean time to first analgesic request in group LT and group LN when compared with group L, which showed a statistically significant difference (P < 0.001). Group LN had the longest duration time and was also statistically significant when compared with group LT (P < 0.001).

With respect to complications, none of the patients included in the study suffered from distal tourniquet pain until its removal from the arm at the end of operation. Postdeflation sedation was assessed at 10-min intervals for 1 h after tourniquet deflation by the RSS (1-6). All patients had score 2 (calm), except for two patients in group LN who were responding to commands (score 3). This was not significant among groups. Three patients in group LT experienced localized skin rash after 5-8 min from injection of local anesthetic mixture. However, it resolved spontaneously. Only one patient developed nausea in group LT after deflation of the cuff and it was treated with ondansetron. These complications were minimal and nonsignificant [Figure 1].

In the present study, there was a statistically significant acceleration in the onsets of both sensory and motor blocks, with significant prolongation of both sensory and motor durations of intravenous local anesthetic block. In addition, there was a highly significant increase in the duration of postoperative analgesia with the addition of tramadol or nalbuphine adjuvants to lidocaine in IVRA. The addition of these adjuvants was accompanied with minimal insignificant side effects. Because of the short duration of action of lidocaine, many adjuvants were used in combination to prolong its analgesic and anesthetic duration [19]. Tramadol, an opioid with weak μ-agonist effect, chemically related to codeine, possesses a local anesthetic activity but of unknown mechanisms [20],[21],[22]. However, it has been proved that tramadol produces its local anesthetic property by blocking sodium channels [23]. It might have a local anesthetic effect similar to lidocaine in addition to its ability to block potassium channels [24],[25],[26]. In several studies, tramadol was shown to exert its analgesic action by preventing the release, blocking the reuptake of norepinephrine, or blocking the reuptake of 5-hydroxytryptamine at α2-adrenergic receptors located in the peripheral nerve endings [27],[28].

Regarding the sensory and motor onsets of the block, in the present study, there was an acceleration in the onset time of both sensory and motor block in both group LT and group LN when compared with group L. However, there was no statistically significant difference between group LT and group LN when compared together. In studies by Acalovschi et al. [29] and Alayurt et al. [30] it has been found that tramadol 100 mg fastened the onset of sensory but not motor block and improved the local anesthetic effect of lidocaine during IVRA. These findings are in agreement with our results.

Nalbuphine is a mixed k-agonist-μ-antagonist opioid with moderate analgesic effect comparable with morphine. Its affinity to k-opioid receptors results in sedation, analgesia, and cardiovascular stability with minimal respiratory depression [7]. There is a great similarity between nalbuphine and butorphanol regarding the chemical nature (synthetic mixed k-agonist-μ-antagonists, mode of action on opioid receptors, and inhibition of serotonin neuronal uptake resulting in augmentation of the spinal inhibitory pathways for pain) [31],[32],[33],[34]. Both are equianalgesic producing sedation and analgesia, with minimal side effects. However, the analgesic duration of nalbuphine is much longer than that of butorphanol [9],[31]. After excessive research in the literature, we did not find any published data studying the effect of nalbuphine when used as an adjuvant in IVRA. Furthermore, only few publications were found on butorphanol in IVRA. However, nalbuphine was studied in details as an adjuvant to local anesthetics in epidural and intrathecal anesthesia [35],[36],[37].

With respect to the duration of sensory and motor blocks, in the present study, there was an increase in the mean duration of both sensory and motor blocks in group LT and group LN compared with group L. This finding was statistically significant. However, when group LT and group LN were compared, there was no significant difference between them. Consistent with our results, Kapral et al. [38] have studied the brachial plexus block and found an increase in the duration of motor block when tramadol was used as an adjuvant to mepivacaine. Those results are in agreement with the findings of our study. In agreement with our findings, Nasr and Waly [5] have studied the effect of tramadol addition to lidocaine as against dexmedetomidine addition to lidocaine in IVRA. They found that there was a statistically significant acceleration of both sensory and motor onsets in the tramadol and dexmedetomidine groups in comparison with the lidocaine group. Bansal et al.[13] studied the effect of butorphanol as an adjuvant to lidocaine in IVRA. Butorphanol addition to local anesthetic resulted in acceleration of the onset times and prolongation of the duration of both sensory and motor blocks compared with the use of lidocaine alone. In the study by Camann et al.[37], assessing the effect of different doses of epidural nalbuphine on the duration of postoperative analgesia, they found that there was a dose-response increase in the duration of postoperative analgesia. These findings were coherent with the results of our study.

Regarding hemodynamic changes, in the present study, there were no significant changes regarding MBP, mean heart rate, and MSpO 2 among the studied groups. In accordance with our study, similar findings were observed in studies by Philip et al.[39] and by Pandit and Kothary [40]. Because of their cardiovascular stability, nalbuphine and butorphanol were used in oral surgery in compromised patients [31]. Nalbuphine has been used intravenously and intramusculary safely during general anesthesia [9],[41],[42]. In agreement with our study, Gupta et al.[34] found that there was a statistically significant increase in the systolic and diastolic blood pressure in the tramadol group compared with the butorphanol group after endotracheal intubation, reflecting cardiovascular stability and attenuation of the pressor response with butorphanol but not with tramadol. In a pilot study on intravenous infusion of nalbuphine and tramadol for postoperative pain control in children, no significant differences were observed between both groups [43]. These findings were in agreement with our results.

With respect to the time to first analgesic request, in our study, the mean time to first analgesic request was significantly prolonged in group LN and group LT when compared with group L. In addition, group LN showed a statistically significant prolongation in the time to first analgesic request when compared with group LT. Consistent to our study, Siddiqui et al.[6] found that tramadol as an adjuvant prolonged the duration of postoperative analgesia. In another study by Ramaiah et al.[19] using butorphanol and parecoxib as adjuvants to lidocaine in IVRA, the duration of postoperative analgesia was significantly increased in the butorphanol group compared with the lidocaine group. However, the analgesic effect of both nalbuphine and tramadol might occur because of systemic absorption after removal of the tourniquet.

With referral to complications, in the present study, only one patient in group LT had nausea after deflation of the cuff. Tramadol increases the release of serotonin and 5-hydroxytryptamine; this was usually accused for the early emesis occurring after drug administration [27]. This explains the cause of skin rash and nausea presented in our study. Gupta et al.[34] found that the incidence of nausea and vomiting was increased in the butorphanol group compared with the tramadol group. However, it was statistically nonsignificant. In contrast to our study, in the study by Moyao-Garcνa et al.[43], nausea occurred in 30% of patients in the tramadol group. In the present study, nalbuphine did not increase the incidence of nausea and vomiting. This is in agreement with the studies by Pandit and Kothary [40] and Onake and Yamamoto [44]. In the study by Bansal et al.[13], 5% of the patients in the butorphanol group experienced nausea. With respect to sedation, all patients were calm (RSS = 2) during the anesthetic procedure and the surgery because of the midazolam injection. However, oversedation (responding to commands, RSS = 3) was observed in two patients in group LN. These complications were minimal and nonsignificant. Our results were compatible with the study by Camann et al.[37] who found that there was a dose-response increase in the incidence of somnolence with different doses of epidural nalbuphine. In the study by Moyao-Garcνa et al.[43], sedation was observed in two patients in the nalbuphine group and in one patient in the tramadol group. These findings match our data. In contrast, Gupta et al.[34] found 16% of patients suffering from nausea in the butorphanol group and 12% of patients in the tramadol group, but with no statistically significant difference. In the study by Stene et al.[45], no side effects were seen because of nalbuphine administration together with cardiovascular stability throughout the study period. Nasr and Waly [5] found that sedation did not occur in any of the patients receiving tramadol in IVRA after removal of the tourniquet. In the present study, 15% of the patients had localized skin rash along the site of injection in group LT because of histamine release by tramadol. However, the rash disappeared at the end of operation without interference. Furthermore, they also found that 30% of the patients had experienced skin rash 5 min after injection of the local anesthetic mixture in IVRA. However, this finding was insignificant. Acalovschi et al.[29] reported the same problem in their study.

The absence of previous studies on nalbuphine in IVRA was the main limitation to our study. Another limitation is that we did not take any blood sample to measure the level of tramadol and nalbuphine in blood to specify the cause of prolonged postoperative analgesia, whether due to systemic absorption or due to local effect. Hence, we recommend further studies to investigate the cause of prolonged postoperative analgesia.

Conclusion

The use of nalbuphine and tramadol as adjuvants to lidocaine in IVRA would accelerate the onset and prolong the duration of both sensory and motor blocks, with minimal insignificant complications. Both tramadol and nalbuphine effects were comparable. However, nalbuphine was proved to be superior to tramadol in prolonging the duration of postoperative analgesia.